About Our Lab
TNT Lab mission and ongoing projects
About Our Lab
The Traumatic Nerve Technologies (TNT) Lab conducts research in many diverse areas. We're taking a multidisciplinary approach to understanding nerve injuries, cell repair strategies, and technologies that assist in prevention, identification, and treatment of nervous tissue injuries.
By advancing the fundamental understanding of the behavioral, morphologic, and molecular mechanistic repercussions accompanying traumatic injuries, we will further identify molecular targets and outcome measures needed for effective treatment strategies.
Traumatic brain injury (TBI) is a large focus of our work and represents a substantial clinical burden worldwide. Patients that sustain a TBI are at greater risk of developing neurodegenerative diseases, in addition to experiencing cognitive and psychological deficits following injury. Few therapeutic strategies have proven successful in mitigating the long-term effects of TBI. This issue is largely attributable to the heterogeneity of mechanical insults that cause TBI, a lack of mechanistic understanding of the cell response to trauma, and failed translation of therapeutics from pre-clinical models to clinical trials.
About Our Research
Our research is focused on veterans. More than 25 percent of veterans returning from Operations Enduring and Iraqi Freedom as well as New Dawn (OEF/OIF/OND) are suffering from closed head injuries due to blast exposure (MaGregor et al., 2011). Blast traumatic brain injury (bTBI) is the second most common cause of injuries from exposure to blast next to amputations. In 2016, there were 13,634 service members that were diagnosed with a TBI, with 86 percent of them categorized as mild (DVBIC, 2016). To further complicate the injury, combat personnel can be exposed to multiple low-level blasts, which could lead to long-term sequelae (Elder et al., 2015). A study by Wilk et al. (2010) surveyed 587 U.S. Army Soldiers returning from Iraq with a self-reported concussion. Of these mild head injuries, 72.2 percent reported a blast mechanism as the cause of injury, highlighting the importance of developing scientifically relevant injury thresholds.
Increasing numbers of veterans are returning from deployment suffering from blast-induced traumatic brain injury (bTBI). A large number of these veterans are exposed to repeated concussive injuries which may lead to long-term neurological impairments. Since bTBI has become a leading cause of disability worldwide, there is a critical need for a greater understanding of the injury mechanisms and long-term neurological dysfunction following single and multiple blast exposure(s)/concussive injuries. Models allow for in-depth examination and evaluation of such exposures and injuries and provide groundwork for later clinical studies involving human participants, further highlighting the importance of and need for this proposed research.
TBI studies have traditionally focused on neuronal dysfunction. However, mechanical disruptions, such as TBI, lead to perturbations in cellular communication and neural networks involving glial cells. Thus, emphasis has shifted to the significance of glial cells, particularly astrocytes, and their role in the progression of TBI.
Astrocytes play a distinct role in traumatic brain injury progression, and thus understanding their fundamental capacity and response to injury are important targets in the way of developing effective treatments. The proposed study incorporates aspects of cell biology and mechanics with signaling networks and computational biology algorithms to understand how force transduction via cell-matrix interactions may contribute to complex sequelae that occur after high rate insult associated with injury across multiple species. This work will create a platform by which we can analyze relevant molecular relationships and potential therapeutic targets in relevant pre-clinical brain injury models.
Complex traumatic brain injury (CTBI) induces distinct pathologic influences on the amygdala that can lead to acute and persistent anxiety. The neurobehavioral sequelae of CTBI may be partly linked to neuroplastic changes that occur in response to mechanical injury and associated stress. Our goal is to expand basic mechanistic insight into CTBI-induced epigenetic and molecular signaling effects on amygdala neuroplasticity and anxiety neural circuitry, with a long-term goal of identifying new molecular targets for future drug development.
This multidisciplinary approach combines epigenetic, histologic, and behavioral assessment techniques to divest and better understand the mechanistic underpinnings that govern amygdala neuroplasticity and aberrant neural circuitry of CTBI-induced anxiety. Linking broad neuromolecular alterations to distinct neurobehavioral phenotypes will help transcend interspecies differences and improve the translatability of acute neurotrauma findings to the clinical setting. Most importantly, this work will establish new pathologic molecular profiles that will guide future mechanistic investigations and identify novel molecular targets that will facilitate potential diagnostic and pharmacotherapeutic development.
Traumatic brain injury continues to be a serious problem in society with 1.7 million occurrences annually in the United States. Currently there have been no neuroprotective drug trials to survive past Phase III clinical trials. Previous in vivo testing involves injury models that are not clinically-relevant, do not include biological variability, and are typically small animal models. There is a need to study TBI in a gyrencephalic models using novel injury devices that simulate human injury conditions.
Complex MR imaging techniques and cognitive/behavioral tests are used to measure changes compared to pre-injury assessments and longitudinally to evaluate possible recovery caused by impact/blast. Histology defines the underlying neuropathology. This data can ultimately be used to develop injury thresholds for human conditions. Cognitive impairments and MR imaging modalities can relate underlying damage to make a link between noninvasive and invasive measurements. These measures can also help ease translation to clinical tools to improve diagnosis and intervention.
Further, addressing biological variability and sex differences will help address some of the limitations in current preclinical models. Ultimately, developing a standardized preclinical model that produces clinically-relevant impact/blast TBI in a gyrencephalic model will better measure drug safety and efficacy. In addition, a well-characterized model can give insight into new drug targets that were missed by previously used in vivo models with non-realistic injury conditions.
Nearly half of all reported cases of acquired epilepsy are caused by traumatic brain injury (TBI), which are often the result of accidental, recreational, and combat-related injuries. These acquired forms of epilepsy are predominant in young adults (18-45 years). Biological factors underlying post-traumatic epilepsy (PTE) as well as predictors for subgroups developing epilepsy remain elusive, as are predictors for subgroups that may present with epilepsy. In addition, prevention of PTE with antiepileptic drugs has been unsuccessful, indicating presence of other, yet unknown mechanisms of epileptogenesis.
Mounting evidence suggests mild repeated TBI pathology contributes to PTE. The influence of cumulative TBI insults on seizures has not been investigated. Further, it is uncertain if blast waves produced by explosions can cause epilepsy. Importantly, the effects of gender on PTE manifestation also require attention. Acquired epilepsy is devastating to patients, as seizures are largely unresponsive to current anti-seizure medications. Seizures significantly impair independent living and cause progressive cognitive decline.
Our team of engineers and neuroscientists at Virginia Tech have joined to address important gaps in PTE knowledge. We will use a military-relevant animal model of blast neurotrauma and post-injury video-electroencephalographic (EEG) monitoring, data analytics, and bioinformatics to accomplish the proposed studies. By sharing expertise across disciplines, we will ensure broad hypothesis testing and robustness of research through the cross-validation of findings.
Blast overpressure can lead to injury of multiple organs, including the brain, lungs, intestines, eyes, and ears. Primary blast injuries describe brain trauma caused by blast wave energy, unlike secondary, tertiary, and quaternary mechanisms, which involve impact from other flying objects or burns. Energy discharged from the blast wave may cause hemorrhaging and ischemia as well as increased oxidative stress in the tissues, which can be associated with the release of reactive oxygen species and matrix degrading enzymes. Blast overpressure is also associated with the loss of synapses and blood brain barrier disruption, which can lead to a chronic inflammatory response and further neural degeneration.
Though the cellular and molecular mechanisms underlying blast TBI are not completely understood, inflammatory processes incite tissue remodeling mediated by monocyte recruitment and differentiation into macrophages. Dynamic changes in macrophage invasion and differentiation play a critical role in the repair process. Macrophages can become “polarized” in response to chemical signals within the damaged tissue to a pro-inflammatory or anti-inflammatory phenotype, depending on the stage of remodeling. This macrophage phenotype imbalance has been implicated in a host of other diseases including cardiac infarction, spinal cord injury, stroke, atherosclerosis, and multiple sclerosis.
Currently, there are no treatments available that address the role of this dynamic inflammatory response following brain injury. Though some anti-inflammatory drugs (i.e. NSAIDs, minocycline) are being investigated as potential TBI treatments, these can be expensive, associated with various side effects, and are plagued by conflicting reports of efficacy. Therefore, a safe and effective TBI treatment remains an unmet medical need.
The leading causes of unintentional TBI are sports-related concussion, falls, motor vehicle accidents and blast exposure, all of which can involve a non-penetrating impact-based event at the mild severity level. TBI is responsible for an estimated $60 billion in direct and indirect medical costs, such as loss of productivity. Not only is the incidence and economic cost of TBI high, no neuroprotective/restorative drug trials have extended past Phase III clinical trials. Thus, novel treatment strategies are needed to improve the outcome of those effected by TBI.
Osteopathy in the cranial field is the study of the anatomic and physiologic mechanisms in the cranium and their interrelationship with the body as a whole, including a system of diagnostic and therapeutic modalities with application to prevent and treat disease. Osteopathic manipulative medicine (OMM) has been used clinically to improve the quality of life for several pathological conditions and injuries; however, limited data is available on the brain’s response to this innovative treatment. The broad, long-term objective of this study is to determine the physiological response of the injured brain to cranial OMM as a treatment strategy.
The data generated as a result of the proposed studies will be motivation for both high impact publications and National Institutes of Health, Department of Defense, and Veterans Affairs research grant applications. Collectively, we will be the first to provide physiological evidence for the observed effects following cranial OMM when used as treatment for mild TBI.
The Virginia Tech Department of Biomedical Engineering and Mechanics is a unique multidisciplinary interface between fundamental mechanics, biomedical science, and real-world applications to enhance the quality of life. Our world-class faculty and students innovate and discover across a continuum of systems, from natural to engineered to medical.
The TNT lab is affiliated with the Institute for Critical Technology and Applied Science, the Virginia Tech Transportation Institute, the Center for Injury Biomechanics, and the Virginia Tech - Wake Forest University School of Biomedical Engineering and Sciences.
Funding for lab research comes from the U.S. Department of Defense, U.S. Department of Veterans Affairs, U.S. Army, U.S. Navy, and the National Science Foundation.